This application for continuation of the Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer at the Johns Hopkins Medical Institutions supports a highly interactive, multidisciplinary, and inter-institutional program. Seven research projects within three research programs, four cores, a career development and a research developmental program are proposed to extend our translational research in colorectal and pancreatic cancer. Research Program 1: Fundamentals for individualizing patient management (Project 1A, Early detection of human colorectal and pancreatic cancer, Drs. Kinzler and Giardiello;1B, Pharmacodiagnostics through molecular clues, Drs. Kern and Laheru). Program 2: Developing and understanding novel therapeutics (2A, Antigen-specific monitoring and therapy in pancreatic Ca, Drs. Jaffee and Laheru;2B, Optimizing and monitoring C. novvi therapy of metastatic colorectal Ca, Drs. Zhou and Diaz). Program 3: Managing and identifying pancreatic neoplasia in the curable stage (3A, Markers for risk in familial pancreatic cancer Hruban, Klein, and Goggins;3B, Screening markers for persons with high pancreatic cancer susceptibility, Drs. Goggins and Hruban;3C, Fundamentals of early and variant pancreatic neoplasia, Drs. Maitra, Kern, and Hruban). The cores support the research programs (Core 1, Administration and Communication, Dr. Scott Kern;2, Human Tissue Research and Logistics, Dr. Ralph Hruban;3, Familial Cancer Registries, Dr. Frank Giardiello;4, Statistics/Bioinformatics, Dr. Steven Goodman. The Career Development Program (Dr. Scott Kern) aids the emergence of new investigators and the Research Developmental Program (Dr. Bert Vogelstein) provides rapid funding of innovative directions.